Methylphenidate Hydrochloride, a scheduled II controlled substance, is currently marketed as a mild central nervous system (CNS) stimulant and the drug of choice for treatment of ADD and ADHA in children. The drug is well absorbed throughout the gastrointestinal tract. However, it has an extremely short half-life, which necessitates a multi-dose treatment regimen for conventional (immediate release) dosage forms such as currently available 5, 10, and 20 mg tablets. Due to high Cmax, oral administration of 10 and 20 mg Ritalin(copyright) is reported to result in notable side effects such as anorexia, weight loss, dizziness, etc. Furthermore, it requires the hyperactive children to be dosed in school thus causing hardship to school authorities as well as parents. The drawback of methylphenidate is that it also produces a euphoric effect when administered intravenously or through inhalation, thus presenting a high potential for substance abuse. Sustained release formulations for once-a-day dosing, such as 20 mg Ritalin SR(copyright) tablets currently available from Novartis and Geneva (generic version), were developed with the objective of providing efficacy for 8 hours, thereby improving compliance and reducing the incidence of diversion. However, there are reports which strongly suggest that the sustained release formulations exhibit a slower onset of action/efficacy compared to the immediate release dosage forms (W.E. Pelham et al., xe2x80x9cSustained Release And Standard Methylphenidate Effects On Cognitive And Social Behavior In Children With Attention Deficit Disorder,xe2x80x9d Pediatrics, Vol. 80, pp 491-501 (1987)).
Recently, OROS(copyright) (methylphenidate HCl) has been approved by FDA. It is a new osmotic controlled release once-a-day oral dosage form with a drug overcoat, that is designed to deliver a portion of the dose for rapid onset of action and deliver the remainder of the dose in a controlled manner for about 10 hours. The manufacturing cost of this complicated dosage form is expected to be very high and hence resulting in a high cost of treatment. Hence, there is a dire need to develop modified release dosage forms with moderate cost of goods and having not only a rapid onset of action but also with a significantly longer duration of action.
U.S. Pat. No. 5,908,850 assigned to Celgene Corporation discloses a method for treating children with the above disability to be treated using a sustained release dosage form containing d-threo-methylphenidate or pharmaceutically acceptable salts thereof thus minimizing hyperactivity and side effects. However, it does not address how it avoids dosing in school, thereby minimizing potential drug abuse.
It has been amply demonstrated that by administering two-bead capsule dosage forms manufactured in accordance with the present invention, therapeutically efficacious plasma concentrations can be achieved for rapid onset of action and maintained for over a 12-hour period, thus eliminating the need to dose children in the school.
An object of the present invention is to provide a method for manufacturing pharmaceutically elegant multi-particulate dosage forms based on the Difficaps(copyright) technology, having two types of bead populationsxe2x80x94one immediate release (IR) Bead and the other extended release (ER) Bead. The IR Bead is designed to release all of the dose over a short period of time, preferably within 30 minutes to act as a bolus dose for rapid onset of action. In contrast, the ER Bead is designed to release the remainder of the total dose as a desired profile over a 12-hour period when dissolution tested in water by USP Apparatus 2 (Paddles @ 50 rpm). Testing to determine in vitro/in vivo correlations can be conducted to predict desirable profiles which can be expected to maintain blood levels of the active agent within a desired therapeutic range over an extended period of time. Another objective is to provide a novel multi-particulate dosage form in order to minimize side effects and eliminate the need to dose children with ADD and ADHD in the school, the release rates from ER Beads and the ratio of IR to ER Beads being determined based on the in vitro/in vivo correlations and efficacy study results obtained.